Summary of Work: A variety of man-made particles, when inhaled, are sources of fibroproliferative lung diseases. A key feature of these diseases is the excessive proliferation of connective tissues cells within the lung. We postulate that the platelet-derived growth factor (PDGF) receptor system is pivotal to the progression of these diseases. Fibrogenic particles cause lung injury and stimulate macrophages to produce inflammatory mediators such as interleukin-1beta (IL-1beta), transforming growth factor beta-1 (TGF-beta-1) and prostaglandin-E2 (PGE2) that modulate PDGF receptor expression. We have shown that IL- 1beta upregulates the PDGF alpha receptor and increases the mitogenic and chemotactic responses of lung fibroblasts to PDGF. In contrast, TGF-beta1 and PGE2 down-regulate the PDGF receptor system and suppress fibroblast growth. The particle-associated agents that mediate the inflammatory responses and subsequent PDGF receptor alteration are endotoxin and metals such as vanadium. Induction of PDGF alpha receptor occurs in vivo following vanadium induced lung injury in rats and precedes fibroblast hyperplasia. IL-1beta-induced expression of the PDGF alpha receptor in vitro is dependent on p38 MAP kinase, but not the extracellular-signal regulated kinases (ERKs) or c-Jun N-terminal kinases (JNKs).Our most recent studies, which have investigated nuclear localization of NFkB (p50/p65 proteins) by gel shift/supershift and the coordinated degradation of IkB-alpha, suggest that IL-1beta does not appear to induce the PDGF receptor through a classic NFkB pathway. Future work will focus on: 1) elucidation of transcription factor(s) which mediate PDGF receptor up-regulation and 2) overexpression of a soluble extracellular PDGF receptor to inhibit the progression of lung fibrosis in rats and mice. It is anticipated that this research will lead to strategies for the intervention pulmonary fibroproliferative lung disease. - fibrosis, lung, macrophages, fibroblast, cytokines, endotoxin, asbestos, metals